tmi-1 and Arthritis--Rheumatoid

Rheumatoid Arthritis (RA) is one of the most common autoimmune inflammatory conditions, affecting approximately 1% of the adult population worldwide. TNF-alpha is a pleitropic, pro-inflammatory cytokine which plays a pivotal role in the origin and progression of RA and other immune mediated disorders. The success of anti-TNF-alpha biological agents proved that inhibition of TNF-alpha could result in effective control of RA. Since the discovery of anti-TNF-alpha biologicals, much efforts have gone into developing an orally bioavailable small size TNF-alpha antagonist. One of the ways to block TNF-alpha in biological fluids is to inhibit TNF-alpha converting enzyme (TACE). This target has been validated in preclinical trials using TACE inhibitors. But, even after more than a decade no single TACE inhibitor has passed the Phase II clinical trials. Very recently, it has been shown that TACE inhibitors could also be used for inhibition of pathogenic EGFR signaling in cancer. Hence, TACE inhibitors could perform a dual role, in curing not only RA but also certain cancerous conditions. Developments in the field have prompted us to review the research work on TACE inhibitors, especially their structure activity relationships and molecular modeling studies.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Arthritis, Rheumatoid; Enzyme Inhibitors; Humans; Models, Molecular; Neoplasms; Structure-Activity Relationship

Tumor necrosis factor (TNF)-alpha is a well validated therapeutic target for the treatment of rheumatoid arthritis. TNF-alpha is initially synthesized as a 26-kDa membrane-bound form (pro-TNF) that is cleaved by a Zn-metalloprotease named TNF-alpha-converting enzyme (TACE) to generate the 17-kDa, soluble, mature TNF-alpha. TACE inhibitors that prevent the secretion of soluble TNF-alpha may be effective in treating rheumatoid arthritis (RA) patients. Using a structure-based design approach, we have identified a novel dual TACE/matrix metalloprotease (MMP) inhibitor 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1). This molecule inhibits TACE and several MMPs with nanomolar IC(50) values in vitro. In cell-based assays such as monocyte cell lines, human primary monocytes, and human whole blood, it inhibits lipopolysaccharide (LPS)-induced TNF-alpha secretion at submicromolar concentrations, whereas there is no effect on the TNF-alpha mRNA level as judged by RNase protection assay. The inhibition of LPS-induced TNF-alpha secretion is selective because TMI-1 has no effect on the secretion of other proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and IL-8. Importantly, TMI-1 potently inhibits TNF-alpha secretion by human synovium tissue explants of RA patients. In vivo, TMI-1 is highly effective in reducing clinical severity scores in mouse prophylactic collagen-induced arthritis (CIA) at 5, 10, and 20 mg/kg p.o. b.i.d. and therapeutic CIA model at 100 mg/kg p.o. b.i.d. In summary, TMI-1, a dual TACE/MMP inhibitor, represents a unique class of orally bioavailable small molecule TNF inhibitors that may be effective and beneficial for treating RA.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Arthritis, Rheumatoid; Cells, Cultured; Disease Models, Animal; Drug Interactions; Enzyme Inhibitors; Female; Humans; Lipopolysaccharides; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Metalloendopeptidases; Mice; Mice, Inbred DBA; Morpholines; RNA, Messenger; Synovial Membrane; Tumor Necrosis Factor-alpha